The purpose of this project is to study physiological and pathological aspects of the renin-angiotensin system, with emphasis in the role of AII in the regulation of aldosterone secretion and circulatory homeostasis. AII mediates the increases in aldosterone secretion during sodium restriction, but the adrenal effects of the peptide are dependent on the sensitivity of the glomerulosa cell to AII. The adrenal sensitivity to AII is increased during sodium restriction and decreased during sodium loading through mechanisms involving the dopaminergic system. In vivo and in vitro studies are in progress to analyze the mechanisms by which dopamine, atrial natriuretic peptide and other factors modulate the actions of angiotensin II in the glomerulosa cell and determine the adrenal sensitivity to AII during changes in soduim intake. The action of AII is highly calcium-dependent, and studies in rat, dog, and bovine adrenal cells and membranes have demonstrtated that nitrendipine binding sites are preferentially located in the glomerulosa zona. Their high correlation with the content of AII receptors suggests a structural relationship between the AII receptor and calcium channels. In addition, dihydropyridine calcium antagonists selectively inhibited Aii and K+ stimulated aldosterone production in rat adrenal glomerulosa cells, indicating a role of voltage-dependent calcium channels in the mechanism of action of these stimulators. Studies in progress also indicate the involvement of calcium-dependent protein kinases in the action of AII. Autoradiographic analysis or angiotensin II binding in frozen brain sections has permitted the identification of AII receptors in specific brain areas involved in circulatory homeostasis, including circumventricular organs, paraventricular nucleus and regions related to the limbic system. Following 48 hr water deprivation, angiotensin II receptors were significantly increased in the subfornical organ (SFO). This increase may represent positive regulation of SFO receptors by the high plasma AII levels during dehydration, with consequent enhancement of the drinking response to water deprivation.